Formation of Irreversible Protein-Binding Metabolites during Microsomal Metabolism of ¹⁴c-Bromobenzene and ¹⁴c-Bromophenol

Abstract

Among hepatotoxic chemicals, bromobenzene is a well known example of a compound thought to induce liver cell necrosis via metabolic activation to protein-binding reactive species. The primarily formed 3,4-epoxide has been suggested to be the reactive metabolite causing hepatotoxicity (Jollow et al., 1974). However, previous studies on the microsomal metabolism of other aromatic hydrocarbons, like 2,2′-dichlorobiphenyl (Hesse et al., 1978), naphthalene (Hesse and Mezger, 1979) and benzene (Tunek et al., 1978), have shown that the major part of covalent binding in vitro originates from reactive intermediates other than the primary epoxides. Studies on the metabolism and binding of naphthol (Hesse and Mezger, 1979) and phenol (Tunek et al., 1978) have demonstrated the high binding capacity of metabolites formed during oxidative metabolism of these phenols. Further, benzene epoxide turned out to be only a weak binding species.